Myelin is a multi-lamellar, lipid-rich structure around neuronal axons that is formed by oligodendrocytes (OLs) in the central nervous system. It is an essential component to ensure timed coordination of neuronal communication, determining higher brain functions. Unfortunately, the myelin is highly sensitive to immune attacks, energy failures and aging. Elucidating the molecular and cellular mechanisms of remyelination after demyelination is a key problem in neuropathology, for aging, for inflammatory white matter diseases such as multiple sclerosis, but also for cognitive dysfunctions.

Strong evidence has been accumulated that activation of the metabotropic γ-aminobutyric acid (GABA) B receptor could play a major role in remyelination, by regulating the differentiation of OLs from their precursor cells (OPCs). We will investigate the role of GABABR in OPCs and OLs in vivo under pathophysiological conditions and establish its modulation. First, by using genetically modified mouse lines, cell sorting as well as in vivo two-photon laser-scanning microscopy, molecular, biochemical and immunohistochemical approaches, we will quantify how the modulation of GABABR expression influences myelination in the healthy brain, in the aged brain and during remyelination after a demyelinating insult. Second, we will perform behavioural experiments to test how genetic and pharmacological manipulation of GABABR function affects higher brain functions.

The objective of current proposal is to investigate the functions of GABABRs in oligodendrocyte lineage cells under physiological and pathological conditions. Based on our preliminary data, we hypothesize that the activation of GABABR in OPCs and OLs determines formation and maintenance of myelin in the healthy brain, and thereby, affects axon function and animal behavior. In addition, genetic and pharmacological manipulation of GABAB receptor function within the oligodendroglia lineage will affect the remyelination after a demyelinating insult, and thereby contribute restoring brain function.